The use of chemotherapeutic drugs as an adjuvant to external beam radiotherapy, surgery, or other treatment modalities is common practice for the treatment of a wide variety of solid tumors. This approach has demonstrated some success in the management of certain cancers. The rationale for combining chemotherapeutic agents with external beam radiotherapy is to radiosensitize the irradiated tumor tissue and/or to target subpopulations of malignant cells that have metastasized from the primary lesion demarcated for beam therapy. Although the tradition of chemoradiotherapy has been practiced for decades and shows promise, some attempts have not succeeded in demonstrating either an added therapeutic benefit or a reduction of normal tissue toxicity. In another approach, radiolabeled chemotherapy agents have been used in an attempt to achieve enhanced cytotoxicity both in human cancer cells and apparently normal hamster fibroblasts. Chemotherapy has also been combined with radioimmunotherapy.
One limitation of chemoradiotherapy is the frequent lack of interaction between chemotherapeutics and ionizing radiation. This often leads to escalation of radiation and drug doses, which in turn, results in elevated normal tissue toxicity. Moreover, lack of specificity of chemotherapy drugs for tumor tissue can result in an insignificant difference in toxicity towards malignant and normal tissues thereby providing no added therapeutic benefit compared to surgery and radiation alone. Despite these limitations, chemoradiotherapy often provides considerable therapeutic benefit. However, observed inconsistencies in treatment outcomes may be due to the widely varying chemotherapeutic drug concentrations employed and radiation absorbed doses achieved. In addition, there is evidence demonstrating that optimization of radiation dose and drug concentration, and the time sequence for administering drugs and radiation play important roles in treatment responses both in vitro and in vivo. Also, regardless of the quality of radiation used, the wide variability in drug toxicity in normal cells of different histologies has to be considered in favor of the most sensitive tissue in chemoradiotherapy. Unfavorable outcomes in therapies involving the use of chemotherapy drugs and radiopharmaceuticals have been attributed to insufficient tumor specificity, poor tumor vascularization, and nonuniformities in agent distribution at the macroscopic, cellular, and subcellular levels. Determination of drug and radionuclide incorporation at the single-cell level has been difficult. As such, estimation of intracellular chemotherapy drug concentration and intra-cellular radioactivity (required to determine radiation absorbed dose to the cell) has largely been restricted to the macroscopic level. Accordingly, it has been difficult to establish a relationship between therapeutic agent incorporation and biologic response.
In addition, the limited success in chemo-radiotherapy of primary solid tumors and metastatic disease is likely due to this lognornnal phenomenon, in which minute subpopulations of cells take up very little or no therapeutic agent. Repopulation by these subpopulations could mask a possible treatment benefit and result in an even more resistant neoplastic form. Thus, to enhance tumor response, there continues to be a need to address the nonuniform, lognormal distribution of chemotherapy drugs and radiopharmaceuticals.
Prediction of tumor and normal-tissue responses in therapeutic nuclear medicine relies heavily on calculation of the absorbed dose. A general formalism was developed by the Medical Internal Radiation Dose (MIRD) Committee of the Society of Nuclear Medicine to calculate absorbed doses from tissue-incorporated radioactivity. However, absorbed-dose specification is complex due to the wide variety of radiations emitted, heterogeneity in activity distribution and biokinetics, and other confounding factors. Following the administration of a radiopharmaceutical, the radioactivity is taken up by tumors (if any) and the various organs within the body and the radioactivity is then eliminated through both biological clearance and physical decay.
The extent to which nonuniform distributions of radioactivity within a small tissue element impact the absorbed dose distribution, and ultimately the biological effect, is strongly dependent on the number, type, and energy of the radiations emitted by the radionuclide. Many radionuclides used in nuclear medicine decay by electron capture and/or internal conversion (e.g. 67Ga, 99mTc, 111In, 123I, 201Tl) and consequently emit a large number of low-energy Auger and conversion electrons. Many of these electrons deposit their energy over subcellular dimensions and therefore produce nonuniform dose distributions. Similarly, the short range of alpha particles in biological tissues (40-100 μm) also leads to nonuniform dose distributions from 223Ra and other alpha particle emitters of potential use in nuclear medicine. Energetic beta emitters such as 90Y have a greater degree of cross-irradiation because their mean range in tissue is at least several hundred microns. However, the nonuniform distribution of these radionuclides invariably leads to nonuniform dose distributions as well. While it is essential to consider the dose distributions that arise from nonuniform distributions of radioactivity, it is also necessary to know whether the dose to a given cell arises from radioactive decays within itself (self-dose) or decays in surrounding cells or other parts of the body (cross-dose). Cellular response to self-dose delivered by a radiopharmaceutical can be considerably different than its response to cross-dose from the same radiopharmaceutical. Accordingly, there is a need for tools and methods that can model biological responses to nonuniform activity distributions encountered in nuclear medicine, to assist in designing therapeutic nuclear medicine treatment strategies for patients undergoing nuclear medicine procedures for cancer therapy.